Single-cell and spatial transcriptomics identify immune–stromal interactions in cardiac allograft vasculopathy
Year: 2026
Type: article
Abstract: Cardiac allograft vasculopathy (CAV) is the leading cause of mortality in heart transplant recipients. Despite the prevalence of CAV, there are no targeted therapeutic options to prevent or reverse disease progression, and patients ultimately require retransplant. CAV is defined by progressive neointimal hyperplasia in donor heart coronary arteries, leading to luminal obliteration and ultimately allograft failure or sudden cardiac death. Although immune and stromal cell interactions are believed to play a key role in CAV pathogenesis, the specific cellular players and molecular signals driving disease remain undefined. In this study, we leverage single-cell RNA sequencing and spatial transcriptomics of human coronary arteries to transcriptionally characterize CAV and define the neointimal microenvironment. We compare arteries with CAV to atherosclerotic coronary artery disease and non-disease controls to identify a unique CAV transcriptional signature. Integration of single-cell RNA sequencing and spatial transcriptomic datasets revealed that modulated vascular smooth muscle cells and macrophage subsets dominate the CAV neointima and suggest that these cells interact to propagate type 1 interferon (IFN)-mediated inflammation. In a mouse CAV model, we demonstrate that interferon blockade with Ruxolitinib significantly reduced the incidence of CAV and prolonged allograft survival. Collectively, this study offers a novel and detailed characterization of the unique cellular and transcriptional landscape of CAV and identify a candidate pathway that may underly CAV pathogenesis, which could serve as a new therapeutic target for this devastating disease.
Source: Nature Cardiovascular Research
Authors: Macee C. Owen, Daniel Yuhang Li, Haewon Shin, Wenduo Gu, Alekhya Parvathaneni, Farid F. Kadyrov, Xiaoran Wang, Maura Sticco-Ivins, Gianni Bonnici, Samantha L. Nelson, Hao Dun, Sariah Hyacinth, Samantha C. Giangrasso, Caroline Chou, Chieh-Yu Lin, Michael T. Cain, Albert Pedroza, Alex Dalal, Karim Sallam, Jack Boyd, Joseph Woo, Junedh M. Amrute, Paul Cheng, Kory J. Lavine, Benjamin J. Kopecky
Language: English
Subfield: Surgery
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: American Heart Association, Boettcher Foundation, Washington University in St. Louis, Children's Discovery Institute, Alvin J. Siteman Cancer Center, Fondation Leducq, National Institutes of Health, Cancer Center, University of Colorado, Center for Cellular Imaging, Washington University, National Heart, Lung, and Blood Institute, National Cancer Institute, National Institute of Allergy and Infectious Diseases, National Institute of Arthritis and Musculoskeletal and Skin Diseases
Awards: G1114310655, Environmental Determinants of Abdominal Aortic Aneurysms: A Critical Next Century Topic, From Locus to Function: Role of ZEB2 in Human Risk of Coronary Artery Disease, G1565180698, G1681817911, G261815350, MACROPHAGE HETEROGENEITY IN HEART FAILURE PROGRESSION AND CARDIAC RECOVERY, G299873027, G3168635882, Screening for Cardiac Amyloidosis in Veterans using EchoNet-lvh in GERiratric patients (SCAVENGER), The Inflammatory-Fibrosis Axis in Ischemic Heart Failure: translating mechanisms into new diagnostics and therapeutics, The Role of Donor Innate Immune Responses in Regulating Alloimmunity after Heart Transplantation, MACROPHAGE ONTOGENY SHIFTS IN ISCHEMIC HEART DISEASE, G4437252597, G4600103388, TCF21 is a causal coronary artery disease gene that modulates coronary smooth muscle phenotypic transition via epigenetic mechanisms, G5176758024, G5746972746, G5890448404, G63402963, G8242737674, Pediatric Cardiovascular and Pulmonary Research Training Program, G9000319192, Specification and Function of Tissue Resident and Recruited Macrophages in Cardiac Remodeling and Heart Failure, Washington University Rheumatic Diseases Research Resource-based Center, Classical dendritic cells (cDC1) govern cardiac allograft tolerance, Dissecting the Role of Donor CCR2- Macrophages During Acute Cellular Rejection After Heart Transplantation, University of Colorado Cancer Center Support Grant, Cancer Center Support Grant, ZEB1 Mediated Coronary Artery Disease Risk in Vascular Smooth Muscle
OpenAlex ID: W7161537146